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Objective This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. Method The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. Results The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P   <  0.001; BARI: OR 1.07, P   <  0.001), baseline CRP (TOFA: OR 1.32, P   =  0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01–1.38, P   =  0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P   =  0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. Conclusion The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the efficacy and safety of tofacitinib in treatment-refractory inflammatory myositis in a real-world clinical setting. Methods All patients with refractory inflammatory myositis treated with tofacitinib from a single urban centre in Vancouver, British Columbia, Canada, were included from June 2016 to December 2022. The medical records of these patients were retrospectively reviewed. Results A total of 41 patients were included, 23 with classic DM, 12 with amyopathic DM (ADM) and six with PM phenotype. The patients failed an average of four to five non-steroidal immunosuppressants before initiation of tofacitinib. In the classic DM and ADM group, tofacitinib offered clinically and statistically significant cutaneous improvement. In all myositis patients including the PM phenotype, no meaningful muscle strength response to tofacitinib was observed. 53.7% of the patients discontinued tofacitinib due to lack of benefit or death. Of the 19 patients who remained on tofacitinib at the conclusion of this study, tofacitinib demonstrated clinically and statistically significant improvement in cutaneous disease activity. Conclusion Tofacitinib appears to be highly effective in targeting cutaneous manifestations in classic DM and ADM; however, minimal benefit in muscle strength in the DM or PM phenotype were observed. [ABSTRACT FROM AUTHOR]

Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory diseases, such as RA, psoriasis, atopic dermatitis and IBD. Several small-molecule JAK inhibitors (JAKis) are now approved for the treatment of various immune-mediated inflammatory diseases. There are, however, key differences between these agents that could potentially translate into unique clinical profiles. Each JAKi has a unique chemical structure, resulting in a distinctive mode of binding within the catalytic cleft of the target JAK, and giving rise to distinct pharmacological characteristics. In addition, the available agents have differing selectivity for JAK isoforms, as well as off-target effects against non-JAKs. Other differences include effects on haematological parameters, DNA damage repair, reproductive toxicity and metabolism/elimination. Here we review the pharmacological profiles of the JAKis abrocitinib, baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib. [ABSTRACT FROM AUTHOR]

Introduction This multicenter, real-world, retrospective cohort study aimed to assess the effectiveness and safety of tofacitinib (TOFA) in rheumatoid arthritis (RA). Material and methods Two hundred nine patients with active RA treated with TOFA, unresponsive to at least 2 conventional synthetic disease-modifying drugs, were recruited. Clinical characteristics were extracted from an electronic registry and supplemented with manual chart review and data linkage with ambulatory care. Drug retention and reasons for discontinuation were evaluated. Results Median (interquartile range) follow-up in the whole sample was 16.9 (5.93–31.7) months. Mean (standard deviation) age was 51.44 (±11.84) years, with female predominance ( n = 168, 80.4%). Only 30 patients (14.4%) had no pre-existing traditional cardiovascular (CV) risk factor at TOFA initiation. Tofacitinib retention rates were high, with median survival estimated at 89.3% at 6 months, 82.4% at 12 months, and 60.4% at 24 months. Ineffectiveness was the primary cause of discontinuation ( n = 50). The rate of adverse events (AEs) was relatively low, with lipid abnormalities, blood count alterations, and infectious events among the most common. No major adverse CV event was reported. The incidence rate of AEs necessitating treatment switch was 60.34 (95% CI: 37–92) per 1,000 per-son-years of follow-up. Presence of multiple (> 3) CV risk factors was associated with lower odds of TOFA retention and treatment effectiveness. Conclusions Tofacitinib demonstrated high retention rates and a favorable safety profile in RA patients, including those with traditional CV risk factors. Tofacitinib may be a valuable treatment option for RA patients when combined with individualized CV risk management. Further studies are warranted to explore the long-term effects of TOFA and its CV impact in larger populations.

Objectives Cardiovascular (CV) morbidity and mortality, and perpetuated synovial angiogenesis have been associated with RA. In our study we evaluated angiogenic factors in relation to vascular inflammation and function, and clinical markers in RA patients undergoing 1-year tofacitinib therapy. Methods Thirty RA patients treated with either 5 mg or 10 mg twice daily tofacitinib were included in a 12-month follow-up study. Eventually, 26 patients completed the study and were included in data analysis. Levels of various angiogenic cytokines (TNF-α, IL-6), growth factors [VEGF, basic fibroblast (bFGF), epidermal (EGF), placental (PlGF)], cathepsin K (CathK), CXC chemokine ligand 8 (CXCL8), galectin-3 (Gal-3) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) were determined at baseline, and at 6 and 12 months after initiating tofacitinib treatment. In order to assess flow-mediated vasodilation, common carotid intima-media thickness (ccIMT) and carotid-femoral pulse-wave velocity, ultrasonography was performed. Synovial and aortic inflammation was also assessed by 18F-fluorodeoxyglucose-PET/CT. Results One-year tofacitinib therapy significantly decreased IL-6, VEGF, bFGF, EGF, PlGF and CathK, while it increased Gal-3 production (P   <  0.05). bFGF, PlGF and NT-proBNP levels were higher, while platelet-endothelial cell adhesion molecule 1 (PECAM-1) levels were lower in RF-seropositive patients (P   <  0.05). TNF-α, bFGF and PlGF correlated with post-treatment synovial inflammation, while aortic inflammation was rather dependent on IL-6 and PECAM-1 as determined by PET/CT (P   <  0.05). In the correlation analyses, NT-proBNP, CXCL8 and Cath variables correlated with ccIMT (P   <  0.05). Conclusions Decreasing production of bFGF, PlGF or IL-6 by 1-year tofacitinib therapy potentially inhibits synovial and aortic inflammation. Although NT-proBNP, CXCL8 and CathK were associated with ccIMT, their role in RA-associated atherosclerosis needs to be further evaluated. [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to compare the incidence rates (IRs) of infectious diseases, major adverse cardiovascular events (MACEs), and malignancies in RA patients treated with tofacitinib, baricitinib or a TNF inhibitor. Methods We retrospectively analysed the cases of 499 RA patients treated with tofacitinib (n  = 192), baricitinib (n  = 104), or a TNF inhibitor (n  = 203). We determined the IRs of infectious diseases and the standardized incidence ratio (SIR) of malignancies and investigated factors related to infectious diseases. After adjusting the clinical characteristic imbalance by propensity score weighting, we compared the incidence of adverse events between the Janus kinase (JAK)-inhibitor and TNF-inhibitor groups. Results The observational period was 959.7 patient-years (PY), and the median observational period was 1.3 years. The IRs within the JAK-inhibitor treatment group were: serious infectious diseases other than herpes zoster (HZ), 8.36/100 PY; HZ, 13.00/100 PY. Multivariable Cox regression analyses revealed independent risk factors: the glucocorticoid dose in serious infectious diseases other than HZ, and older age in HZ. Two MACEs and 11 malignancies were identified in JAK-inhibitor–treated patients. The overall malignancy SIR was (non-significantly) higher than that of the general population (1.61/100 PY, 95% CI: 0.80, 2.88). The IR of HZ in the JAK-inhibitor–treated group was significantly higher than the TNF-inhibitor-treated group, but there were no significant differences in the IRs of other adverse events between the JAK-inhibitor–treated group and the TNF-inhibitor–treated group, or between the treatment groups of the two JAK inhibitors. Conclusions The infectious disease IR in RA was comparable between tofacitinib and baricitinib, but the IR for HZ in these treatment groups was high compared with that in the TNF inhibitor treatment group. The malignancy rate in the JAK-inhibitor-treated group was high but not significantly different from that of the general population or that of the TNF-inhibitor–treated group. [ABSTRACT FROM AUTHOR]

The field of rheumatology has experienced dozens of novel drug approvals in the past two and a half decades, but the regulatory mechanisms underpinning these decisions are not well understood. In the USA, the Food and Drug Administration (FDA) evaluates the safety and efficacy of novel drugs through the New Drug Application (NDA) process. When additional content expertise is required to evaluate scientific or technical matters, the FDA may convene Human Drug Advisory Committees. To better understand the landscape of rheumatology NDAs and the FDA use of advisory committees, we performed a review of all rheumatic disease drug applications from 1996 to 2021 that were granted approval by the FDA. Our review identified 31 NDAs, seven of which utilized an advisory committee. The indications for using advisory committees and their influence on ultimate approvals was not clear. Recommendations to improve transparency and increase public trust in FDA decisions are provided. [ABSTRACT FROM AUTHOR]

Objectives To describe the use of baricitinib and tofacitinib by Swedish RA patients and to compare their effectiveness with that of biologic DMARDs (bDMARDs). Methods RA patients who initiated baricitinib (n  = 1420), tofacitinib (n  = 316), abatacept (n  = 1050), IL-6 inhibitors (IL-6is; n  = 849), rituximab (n  = 1101) or TNF inhibitors (TNFis; n  = 6036) between January 2017 and November 2019 were followed for a minimum of 1 year using data from several linked Swedish national registers. Proportions reaching a good EULAR 28-joint DAS (DAS28) response, HAQ Disability Index (HAQ-DI) improvement >0.2 units and Clinical Disease Activity Index (CDAI) remission were compared at 1 year, imputing discontinued treatments as 'non-response'. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to 3 months after treatment initiation. Results On average, baricitinib, and particularly tofacitinib, were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted 1 year response proportions were consistently lower on TNFi compared with baricitinib, with differences of −4.3 percentage points (95% CI −8.7, 0.1) for good EULAR response, −9.9 (−14.4 to −5.4) for HAQ-DI improvement and −6.0 (−9.8 to −2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to 3 months supported the 1 year findings. Conclusions Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures. [ABSTRACT FROM AUTHOR]

Objective To evaluate the risk of venous thromboembolism (VTE) with tofacitinib compared with TNFis in patients with RA. Methods RA patients initiating tofacitinib or a TNFi without use of any biologic or tofacitinib any time prior were identified from IBM 'MarketScan' (2012–18), Medicare (parts A, B and D, 2012–17) or 'Optum' Clinformatics (2012–19) and followed until treatment discontinuation, treatment switch, insurance disenrollment or administrative censoring. The primary outcome, VTE, was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. A Cox proportional hazards model provided hazard ratio (HR) and 95% CIs after accounting for confounding through propensity score fine-stratification weighting. HRs were pooled across databases with inverse variance meta-analytic method. Results A total of 42 201, 25 078 and 20 374 RA patients were identified from MarketScan, Medicare and Optum, respectively, of whom 7.1, 7.1 and 9.7% were tofacitinib initiators. The crude incidence rates per 100 person-years (95% CI) were 0.42 (0.20–0.77) and 0.35 (0.29–0.42) in MarketScan, 1.18 (0.68–1.92) and 0.83 (0.71–0.97) in Medicare, and 0.19 (0.04–0.57) and 0.34 (0.26–0.44) in Optum for tofacitinib and TNFis, respectively. Propensity score-weighted HRs showed no significant differences in the risk of VTE between tofacitinib and TNFis in any database with a pooled HR (95% CI) of 1.13 (0.77–1.65). Conclusion Overall, VTE occurred infrequently (<1 per 100) in a total of 87 653 RA patients initiating tofacitinib or a TNFi. We observed no evidence for an increased risk of VTE for tofacitinib vs TNFis in RA patients. [ABSTRACT FROM AUTHOR]

Objectives To evaluate real-world efficacy of approved JAK inhibitors (JAKi) tofacitinib and baricitinib in a large, single-centre cohort of RA patients across the treatment pathway, including those refractory to multiple biologic drugs. Methods All RA patients, treated with tofacitinib (from time of compassionate access scheme) or baricitinib since approval in 2017 had DAS28-CRP scores and components recorded at baseline, 3 and 6 months (with retrospective data for compassionate access scheme). Efficacy was evaluated in the total cohort, each treatment group, and subgroups of number of prior biologic classes failed. Results One hundred and fifteen patients were treated with a JAKi (tofacitinib 54, baricitinib 69, 8 both); 76.4% female; mean (s. d.) age 57.3 (14.3) years. On average patients had received three previous bDMARDs; 11 (9.6%) were bDMARD naïve. Combined group baseline DAS28-CRP (s. d.) 5.62(1.14) improved by 1.49(1.44) and 1.67(1.61) at 3 and 6 months, respectively, comparable in individual JAKi groups; with 24% in at least low disease activity at 3 months. The biggest improvement was observed in the biologic-naïve group (mean DAS28-CRP improved from 5.16–2.14 after 6 months); while those with prior exposure to minimum three bDMARD classes had DAS28-CRP improvement of >1.2. Five out of 8 patients treated with both JAKi sequentially responded. Twelve patients previously unresponsive to IL-6 blockade responded to JAKi. No unexpected safety events were recorded. Two cases of venous thromboembolism were observed. Conclusion JAK inhibition is effective in a real-world population of RA patients, including in a subset of patients refractory to multiple previous bDMARDs. [ABSTRACT FROM AUTHOR]

Objectives To analyse the effectiveness of tofacitinib for the treatment of refractory skin thickening in dcSSc. Methods Data from 10 patients with dcSSc treated with tofacitinib (5 mg twice daily) were analysed. A total of 12 dcSSc patients treated with intensive conventional immunosuppressants were selected as the historical comparator group. A clinically relevant response was defined as a decrease in the modified Rodnan skin score (mRSS) of >5 points and ≥25% from baseline. Clinical indicators were compared between the two groups to evaluate the effect of tofacitinib. Results The mRSS significantly improved the first month after tofacitinib treatment, with a mean change in the mRSS of −3.7 (95% CI −5.52, −1.88; P  = 0.001) and greater than the comparators at 6 months [−10.0 (95% CI −14.74, −5.26) vs −4.1 (95% CI −7.49, −0.73), P  = 0.026]. Tofacitinib-treated patients had a significantly shorter response time than the comparators (P  = 0.015 by log-rank test), with overall response rates of 20% (2/10) vs 0% (0/12) and 60% (6/10) vs 16.7% (2/12) at 1 and 3 months, respectively. Conclusion Our results indicate that tofacitinib may be as effective as or even better than intensive conventional immunosuppressants, with a quicker and higher response rate in refractory dcSSc patients with progressive skin thickness. [ABSTRACT FROM AUTHOR]

Objectives JDM is a rare autoimmune inflammatory muscle disease with a pronounced IFN signature. Treatment for children with JDM has improved over the years with the use of steroids and immunosuppressive agents. However, there remains a subset of children who have refractory disease. Janus kinase and type I IFN signalling production are suspected to contribute to the pathogenesis of JDM. Our pilot study investigated the use of tofacitinib, a Janus kinase inhibitor, in refractory JDM cases to provide new therapeutic options for better treatment. Methods Refractory JDM was defined as patients who failed two or more steroid sparing agents or high-dose steroids. Tofacitinib was given to three refractory JDM patients with a dose of 5 mg twice per day for at least 6 months. Core set measures defined by Pediatric Rheumatology International Trials Organization were evaluated at month 0, 3 and 6 along with other systemic evaluations. A literature review was conducted to identify all the cases using Janus kinase inhibitors in JDM. Results All three subjects tolerated and responded well to tofacitinib with significant improvement in Child Myositis Assessment Scale, manual muscle testing-8, physician global disease activity and inflammatory indices without occurrence of severe adverse events. Conclusion This pilot study showed improvement of muscle strength, resolution of cutaneous lesions, increased daily quality of life and successful tapering of steroids when tofacitinib used in selected cases. Tofacitinib can be considered with caution when treating refractory JDM cases. Further randomized controlled trials are warranted to assess its efficacy in JDM. [ABSTRACT FROM AUTHOR]

Objective Altered homeostasis of salivary gland (SG) epithelial cells in Sjögren's syndrome (SS) could be the initiating factor that leads to inflammation, secretory dysfunction and autoimmunity. Autophagy is an important homeostatic mechanism, whose deficiency is associated with inflammation and accumulation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) components. We aimed to evaluate whether autophagy is altered in labial SG (LSG) epithelial cells from primary SS (pSS) patients and whether this contributes to inflammation through the JAK–STAT pathway. Furthermore, we investigated the anti-inflammatory effect of the JAK inhibitor tofacitinib in autophagy-deficient (ATG5 knockdown) three-dimensional (3D)-acini. Methods We analysed LSG biopsies from 12 pSS patients with low focus score and 10 controls. ATG5-deficient 3D-acini were generated and incubated with IL-6 in the presence or absence of tofacitinib. Autophagy markers, pro-inflammatory cytokine expression, and JAK–STAT pathway activation were evaluated by PCR or western blot, along with correlation analyses between the evaluated markers and clinical parameters. Results LSG from pSS patients showed increased p62 and decreased ATG5 expression, correlating negatively with increased activation of JAK–STAT pathway components (pSTAT1 and pSTAT3). Increased expression of STAT1 and IL-6 correlated with EULAR Sjögren's syndrome disease activity index and the presence of anti-Ro antibodies. ATG5-deficient 3D-acini reproduced the findings observed in LSG from pSS patients, showing increased expression of pro-inflammatory markers such as IL-6, which was reversed by tofacitinib. Conclusion Decreased expression of ATG5 in LSG epithelial cells from pSS patients possibly contributes to increased inflammation associated with JAK–STAT pathway activation, as evidenced in ATG5-deficient 3D-acini. Interestingly, these results suggest that tofacitinib could be used as an anti-inflammatory agent in pSS patients. [ABSTRACT FROM AUTHOR]

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis). Methods In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis. Results For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n  = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n  = 269). Conclusion Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years. Trial registration ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661. [ABSTRACT FROM AUTHOR]

Objectives Small molecule tyrosine kinase inhibitors [smTKI, comprising mostly of Janus kinase (JAK) and to a lesser extent, spleen tyrosine kinase (SyK) inhibitors] modulate the cytokine receptor-mediated intracellular signal cascade, and are an effective treatment for autoimmune diseases and malignancies. As smTKI are novel, long-term safety is uncertain. Due to increasing use, characterization of their true adverse event profile is critical. Methods We performed a systematic review and meta-analysis of all published trial data on the pulmonary and serious adverse effects of smTKIs in autoimmune disease. EMBASE, MEDLINE, CENTRAL and Pneumotox databases were searched up to April 2019 for randomized controlled trials, observational studies and post marketing surveillance, comparing any smTKI with placebo or another therapy, or as monotherapy at different doses. Primary outcomes comprised of any respiratory complications including upper and lower respiratory tract infections (URTI, LRTI), influenza, pneumonia, opportunistic respiratory infections, drug-induced interstitial lung disease, pulmonary embolism and lung neoplasm. Results We identified 4667 citations for screening, and selected 319 studies for full text review. Seventy-nine studies were analysed, including 47 randomized controlled trials, 25 observational studies and seven post-marketing surveillance studies, comprising 159 652 participants. There were significantly increased risks of URTI [risk difference (RD) 0.03; 95% CI: 0.01, 0.05; P  = 0.00; 36 studies, 14 724 participants], LRTI (RD 0.01; 95% CI: 0.00, 0.02; P  = 0.02; 24 studies, 12 302 participants), influenza (RD 0.01; 95% CI: 0.00, 0.01; P  = 0.04; 22 studies, 10 684 participants), and pneumonia (RD 0.00; 95% CI: 0.00, 0.01; P  = 0.02; 33 studies, 15 511 participants). No increased risk was found for other respiratory complications, including pulmonary embolism. Conclusion SmTKI increases the risk of non-opportunistic respiratory infections compared with placebo. The risk of any serious pulmonary adverse events is low. [ABSTRACT FROM AUTHOR]

Objectives To describe characteristics, treatment patterns and persistence in patients with RA treated with tofacitinib, an oral Janus kinase inhibitor, in Canadian clinical practice between 1 June 2014 and 31 May 2017. Methods Data were obtained from the tofacitinib eXel support programme. Baseline demographics and medication history were collected via patient report/special authorization forms; reasons for discontinuation were captured by patient report. Treatment persistence was estimated using Kaplan–Meier methods, with data censored at last follow-up. Cox regression was applied to analyse baseline characteristics associated with treatment discontinuation. Results The number of patients with RA enrolled from 2014 to 2017 was 4276; tofacitinib utilization increased during that period, as did the proportion of biologic (b) DMARD-naïve patients prescribed tofacitinib. Of patients who initiated tofacitinib, 1226/3678 (33.3%) discontinued, mostly from lack of efficacy (35.7%) and adverse events (26.9%). Persistence was 62.7% and 49.6% after 1 and 2 years of treatment, respectively. Prior bDMARD experience predicted increased tofacitinib discontinuation (vs bDMARD-naïve, P < 0.001). Increased retention was associated with older age (56–65 years and >65 years vs ⩽45 years; P < 0.05), and time since diagnosis of 15 to <20 years (vs <5 years; P < 0.01). In bDMARD-naïve, post-1 bDMARD, post-2 bDMARD and post-⩾3 bDMARD patients, median survival was >730, 613, 667 and 592 days, respectively. Conclusion Since 2014, tofacitinib use in Canadian patients with RA increased, especially among bDMARD-naïve/post-1 bDMARD patients. Median drug survival was ∼2 years. Likelihood of persistence increased for bDMARD-naïve (vs bDMARD-experienced) patients and those aged ⩾56 (vs ⩽45) years. [ABSTRACT FROM AUTHOR]

Objective RA is a chronic inflammatory disease characterized by lymphocyte infiltration and release of inflammatory cytokines. Previous studies have shown that treatment with Janus kinase inhibitors, such as tofacitinib, increased the incidence rate of herpes zoster compared with conventional DMARDs. Therefore, this study aimed to investigate the effect of tofacitinib on the varicella-zoster-virus (VZV)-specific T cell immune response. Methods The effect of tofacitinib on the VZV-specific T cell immune response was determined by evaluating the IFNγ production, the proliferative capacity, the VZV-induced differentiation into effector and memory T cells, the expression of activation marker CD69 and helper T cell type 1 (Th1)-characteristic chemokine receptors, such as CXCR3 and CCR5, as well as cytotoxic activity (perforin and granzyme B expression) of CD4+ T cells of patients with RA compared with healthy donors upon stimulation with VZV antigen in vitro. Results Tofacitinib significantly reduced the IFNγ production, proliferation, activation, and CXCR3 expression of VZV-specific CD4+ T cells in a dose-dependent manner in short- and long-term lymphocyte culture. No effect on the distribution of naive, effectors or memory, or on the expression of perforin or granzyme B by VZV-specific CD4+ T cells was observed. Conclusion This study showed that tofacitinib significantly modulated the Th1 response to VZV. The poor VZV-specific cellular immune response in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response. [ABSTRACT FROM AUTHOR]

Objectives Some patients with cutaneous DM demonstrate incomplete responses to conventional therapy while some, including those with extra-cutaneous manifestations, experience disease recurrences. Janus kinase/signal transducers and activators of transcription pathway inhibition has been reported to mitigate IFN signalling, which is thought to contribute to disease pathogenesis in DM. Four cases of refractory DM responsive to tofacitinib have been reported in the literature. Our case series investigated the use of tofacitinib in refractory cutaneous DM. Methods Our case series includes four subjects with refractory DM who received tofaticinib after failure of several immunosuppressive and immunomodulatory agents. Results All four subjects responded well to tofacitinib with significant improvement in cutaneous and extra-cutaneous manifestations. Conclusion Tofacitinib can improve cutaneous and inflammatory articular manifestations in refractory DM. [ABSTRACT FROM AUTHOR]

To facitinib and baricitinib are two of the currently available Janus kinase (JAK) inhibitors for the treatment of patients with RA. Randomized controlled trials have shown that these JAK inhibitors are as efficacious as biological DMARDs. Safety profiles of these JAK inhibitors in randomized controlled trials and their long-term extension studies have been demonstrated; however, real world evidence remains to be established to bridge the gap between randomized controlled trials and rheumatology clinics. Fundamentally, no difference in the screening, prevention, and monitoring of infections between JAK inhibitors and biological DMARDs exists. However, increased risk of herpes zoster is probably common to all JAK inhibitors. No indication of increased risk for malignancy in patients with RA treated with JAK inhibitors has been reported. To evaluate risks of relatively rare serious adverse events such as thromboembolic events, gastrointestinal perforation, and interstitial lung disease in clinical settings, accumulation of cases with these events are needed. Continuous pharmacovigilance activity is absolutely warranted to establish the safety of JAK inhibitors in patients with RA and other rheumatic diseases. [ABSTRACT FROM AUTHOR]

Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs. [ABSTRACT FROM AUTHOR]

Objective Tofacitinib is an oral Janus kinase inhibitor for treatment of RA. We compared tofacitinib modified-release (MR) 11 mg once daily (QD) with tofacitinib immediate-release (IR) 5 mg twice daily (BID) in Japanese patients with RA and inadequate response to MTX. Methods Phase III, randomized, double-blind, double-dummy, 12-week study. Patients were randomized to tofacitinib MR 11 mg QD (n = 104) or IR 5 mg BID (n = 105), with stable MTX. Compliance was based on returned pill counts. The primary objective was to demonstrate non-inferiority of MR 11 mg QD to IR 5 mg BID. Non-inferiority was declared if the upper bound of the two-sided 95% CI for the difference in change from baseline in DAS28-4(CRP) at week 12 was <0.6. Results At week 12, with tofacitinib MR 11 mg QD and IR 5 mg BID, respectively, the change from baseline in least squares mean DAS28-4(CRP) was −2.43 and −2.85; the mean difference was 0.43 (95% CI 0.17, 0.69). Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met. Improvement of DAS28-4(CRP) ⩾1.2 was observed in 89 and 85% of patients, respectively, corresponding to a clinically important, significant change in both groups. The frequency of adverse events (52.9 and 51.4%, respectively) and serious adverse events (4.8 and 3.8%, respectively) was generally similar between treatments. No deaths were reported. Conclusion Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met in this study. However, clinically meaningful improvements in RA were observed with both tofacitinib formulations in Japanese patients. The safety profile was similar with both formulations. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02281552. [ABSTRACT FROM AUTHOR]

Objective We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment. Methods Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed. Results Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection. Conclusion Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD. [ABSTRACT FROM AUTHOR]

Objectives Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ⩾2.5 for SI joint and ⩾5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS treated with tofacitinib or placebo, and correlation with clinical responses. Methods Adult AS patients in a 12-week phase 2 study (n = 207) were randomized 1: 1: 1: 1 to tofacitinib 2, 5 or 10 mg twice daily (BID) or placebo. MIC in SPARCC SI joint and spine scores were assessed for patients with available MRI data (N = 164; 79%). Clinical endpoints at week 12, including Assessment of SpondyloArthritis international Society 20% improvement (ASAS20), were compared between patients achieving/not achieving MIC. Results A greater proportion of patients achieved MIC with tofacitinib 2, 5 and 10 mg BID vs placebo for SI joint (28.6, 38.6, 29.6 vs 11.8%) and spine scores (29.3, 36.4, 40.9 vs 11.8%). Generally, a greater proportion of patients treated with tofacitinib 2, 5 and 10 mg BID or placebo, respectively, who achieved MIC for SI joint and spine scores achieved ASAS20 (SI joint: 75.0, 88.2, 69.2, 75.0%; spine: 91.7, 85.7, 72.2, 75.0%) vs patients who did not achieve MIC (SI joint: 51.7, 84.0, 58.1, 48.3%; spine: 46.4, 85.7, 53.8, 48.3%). Numerically greater responses were seen in those patients achieving vs not achieving MIC across a range of other efficacy assessments. Conclusion Approximately one-third of tofacitinib-treated AS patients experienced clinically meaningful reductions in spinal MRI inflammation at week 12. Patients achieving MIC for MRI inflammation had greater clinical response. [ABSTRACT FROM AUTHOR]

Objectives. RA causes high disability levels and reduces health-related quality of life, triggering increased costs and risk of unemployment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. These post hoc analyses of phase 3 data aimed to assess monthly medical expenditure (MME) and risk of job loss for tofacitinib treatment vs placebo. Methods. Data analysed were from two randomized phase 3 studies of RA patients (n = 1115) with inadequate response to MTX or TNF inhibitors (TNFi) receiving tofacitinib 5 or 10 mg twice daily, adalimumab (one study only) or placebo, in combination with MTX. Short Form 36 version 2 Health Survey physical and mental component summary scores were translated into predicted MME via an algorithm and concurrent inability to work and job loss risks at 6, 12 and 24 months, using Medical Outcomes Study data. Results. MME reduction by month 3 was $100 greater for tofacitinib- than placebo-treated TNFi inadequate responders (P < 0.001); >20 and 6% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ≽16%, and risk of future job loss decreased ~20% (P < 0.001 vs placebo). MME reduction by month 3 was $70 greater for tofacitinib- than placebo-treated MTX inadequate responders (P < 0.001); ≽23 and 13% reductions from baseline, respectively. By month 3 of tofacitinib treatment, the odds of inability to work decreased ≽31% and risk of future job loss decreased ≽25% (P < 0.001 vs placebo). Conclusion. Tofacitinib treatment had a positive impact on estimated medical expenditure and risk of job loss for RA patients with inadequate response to MTX or TNFi. [ABSTRACT FROM AUTHOR]

Objective. To determine whether tofacitinib can be discontinued in patients with RA who achieve low disease activity (LDA). Methods. RA patients with LDA after tofacitinib treatment in a phase III and long-term extension study were enrolled in this multicentre, non-randomized, open, prospective, observational study. The decision of discontinuation or continuation of tofacitinib was determined based on patient-physician decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib-free at post-treatment week 52. Clinical outcome was compared between those who continued and those who discontinued tofacitinib. The last observation carried forward method was used for patients who could not discontinue tofacitinib before week 52. Results. Of 64 patients, 54 discontinued and 10 continued tofacitinib therapy. At post-treatment week 52, 20 of the 54 patients (37%) of the discontinuation group remained tofacitinib-free without disease flare. Disease activity at post-treatment week 52 was higher in the discontinuation group than the continuation group. Among the discontinuation group, the RF titre at baseline was significantly lower in patients who remained tofacitinib-free than those who did not (40 vs 113 U/ml). In fact, a higher proportion of patients with lower RF remained tofacitinib-free at week 52 compared with those with higher RF at baseline. In patients who could not achieve tofacitinib-free status, re-initiation of tofacitinib or other biologics improved disease activity. Conclusion. It is possible to discontinue tofacitinib without flare in about a third of patients with RA. A low RF predicts maintenance of LDA after discontinuation of tofacitinib. [ABSTRACT FROM AUTHOR]

Objectives. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The aim of this analysis was to characterize changes in haematological parameters following tofacitinib treatment, and to compare changes in haemoglobin with markers of disease activity, fatigue and vitality. Methods. Changes in neutrophil counts, lymphocyte counts and haemoglobin levels were analysed in patients with RA from six phase 3 randomized controlled trials (n = 4271) of tofacitinib 5 or 10mg bd, placebo or active comparators of up to 24 months' duration, and two long-term extension (LTE) studies (n = 4858) of tofacitinib of up to 84 months' duration. Disease activity markers included CRP and ESR. Fatigue and vitality were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Short Form Health Survey-36 vitality domain scores. Results. In phase 3 studies, mean neutrophil and lymphocyte counts decreased and mean haemoglobin levels increased in all tofacitinib treatment groups. Haemoglobin levels and neutrophil counts stabilized in the LTE studies, while lymphocyte count decreases stabilized at approximately month 48. Increased haemoglobin was associated with decreased ESR and CRP levels. Clinically meaningful reductions in haemoglobin levels (≥3g/dl from baseline or haemoglobin ≤7g/dl) occurred in <1.0% of patients in all treatment groups. FACIT-F and Short Form Health Survey-36 vitality scores were weakly correlated with haemoglobin levels. Conclusion. Small changes in haematological parameters were seen with tofacitinib treatment, which stabilized over time in the LTE studies. Changes in haemoglobin levels, although associated with changes in ESR and CRP, were not associated with fatigue or vitality. [ABSTRACT FROM AUTHOR]

Objective. To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX. Methods. In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep). Results. At month 3, tofacitinib 10mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ≥ minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ≥ minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10mg BID and similar between tofacitinib 5mg BID and adalimumab. Conclusion. Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10mg BID and adalimumab that were significantly superior to placebo. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study was to assess the risk of active tuberculosis (TB) in patients with immune-mediated inflammatory diseases treated with biologics and tofacitinib in randomized controlled trials (RCTs) and long-term extension (LTE) studies.Methods. A systematic review of the English-language literature by was performed by searching the Medline, Embase, Cochrane and Web of Knowledge databases. The search strategy focused on synonyms of diseases, biologics and tofacitinib. Data from RCTs were combined to assess the rate of TB using a random effects model. The incidence rate (IR) of TB and its association with disease, location and treatment were assessed in LTE studies.Results. The search captured 11 130 articles and abstracts. One-hundred RCTs (75 000 patients) and 63 LTE studies (80 774.45 patient-years) met the inclusion criteria. There were 31 TB cases with TNF inhibitors, 1 with abatacept and none with rituximab, tocilizumab, ustekinumab or tofacitinib. The odds ratio for TNF inhibitors was 1.92 (95% CI 0.91, 4.03, P = 0.085). In LTE studies, the IR of TB was >40/100 000 with tofacitinib and all biologics except rituximab. IR was higher in RA patients with anti-TNF monoclonal antibodies [307.71 (95% CI 184.79, 454.93)] than in those with rituximab [20.0 (95% CI 0.10, 60)] and etanercept [67.58 (95% CI 12.1, 163.94)] or AS, PsA and psoriasis with etanercept [60.01 (95% CI 3.6, 184.79)]. The IR of TB was higher in high-background TB areas.Conclusion. RCTs are not sensitive enough to assess the risk of reactivation of latent TB infection (LTBI). Disease, treatment and background TB rate are associated with different frequencies of active TB. The benefit/risk balance of preventing reactivation of LTBI in different backgrounds should be considered in clinical practice. [ABSTRACT FROM PUBLISHER]

Objectives. To assess the effects of tofacitinib on T lymphocytes in RA patients with a special focus on efficacy and infectious adverse events (iAEs). Methods. Forty-four RA patients participated in 12-month phase II/III randomized clinical trials and an open-label extension trial. Peripheral lymphocyte subsets and in vitro CD4+ T lymphocyte proliferation were measured in 23 patients of 44 at baseline and at the end of the 12-month trial. Results. Forty-four patients [35 females, age 54.3 years, disease duration 84.3 months, simplified disease activity index (SDAI) 36.5, CRP 24.9 mg/l, ESR 53 mm/h, MMP-3 284 pg/ml, RF 172.6 IU/ml, neutrophil count 4842 per μl, lymphocyte count 1410 per μl] were treated with tofacitinib. At the end of the study, the SDAI improved to 6.2, but the peripheral lymphocyte count and absolute numbers of CD4+ and CD8+ subpopulations did not change during this period. However, CD4+ T lymphocyte proliferation was suppressed, which correlated with the improvement in SDAI, but not with iAEs (n = 19) during the 12-month treatment. Receiver operating characteristic analysis identified a CD8+ T lymphocyte count ≤211 per μl at baseline as a significant predictor of clinically significant iAEs. Conclusion. The efficacy of tofacitinib is mediated through the suppression of CD4+ T lymphocyte proliferation without affecting the absolute number of these cells in the periphery. A low CD8+ T cell count at baseline correlated with the development of iAEs during the treatment of RA patients. [ABSTRACT FROM AUTHOR]

Advances in the treatment of RA in the past decade have been achieved mainly by using combinations of different conventional and biologic DMARDs. However, until now no final victory has been achieved over this organ damaging and potentially life-threatening systemic autoimmune disease. Few patients, notably those with established disease, stay in remission permanently, even using advanced treatment concepts. Thus novel approaches, especially for patients resistant to biologics, are urgently needed. Pro-inflammatory signalling pathways beyond the level of cytokines and receptors have been intensively elaborated and provide such potential targets. This review focuses on the development of new small molecule inhibitors of Janus kinases in clinical trials in RA. [ABSTRACT FROM PUBLISHER]

Orally available small molecule compounds have recently been developed for the treatment of RA, and inhibitors of signalling cascades, specifically inhibitors of kinases, have reached advanced stages of clinical development. The p38 mitogen-activated protein kinase blockers have shown poor clinical response despite encouraging preclinical data. In contrast, inhibitors of the non-receptor tyrosine kinases, spleen tyrosine kinase and janus kinase 3, have demonstrated a significant clinical efficacy together with an acceptable safety profile. We herein present a review on published preclinical and clinical data on these new drugs. [ABSTRACT FROM PUBLISHER]